Liquid pharmaceutical formulations of palonosetron

ABSTRACT

The present invention relates to shelf-stable liquid formulations of palonosetron for reducing chemotherapy and radiotherapy induced emesis with palonosetron. The formulations are particularly useful in the preparation of intravenous and oral liquid medicaments.

This is a continuation of U.S. Ser. No. 13/902,299, filed May 24, 2013,which is a continuation of U.S. Ser. No. 13/901,437, filed May 23, 2013(now U.S. Pat. No. 8,598,219), which is a continuation-in-part of U.S.Ser. No. 13/087,012 filed Apr. 14, 2011 (now U.S. Pat. No. 8,518,981),which is a continuation of U.S. Ser. No. 11/186,311 filed Jul. 21, 2005(now U.S. Pat. No. 7,947,724), which is a continuation ofPCT/EP04/000888, filed Jan. 30, 2004, which claims priority to U.S.Provisional Application 60/444,351, filed Jan. 30, 2003. The content ofthese applications is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to shelf-life stable liquid formulationsof palonosetron that are especially useful in the preparation ofinjectable and oral medicaments.

BACKGROUND OF THE INVENTION

Emesis is a devastating consequence of cytotoxic therapy, radiotherapy,and post-operative environments that drastically affects the quality oflife of people undergoing such treatments. In recent years a class ofdrugs referred to as 5-HT₃ (5-hydroxytryptamine) receptor antagonistshas been developed that treat such emesis by antagonizing cerebralfunctions associated with the 5-HT₃ receptor. See Drugs Acting on5-Hydroxytryptamine Receptors: The Lancet Sep. 23, 1989 and referencescited therein. Drugs within this class include ondansetron, granisetron,alosetron, tropisetron, and dolasetron. These 5-HT₃ antagonists areoften administered intravenously shortly before chemotherapy orradiotherapy is initiated, and can be administered more than once duringa cycle of chemotherapy or radiotherapy. In addition, they are oftensupplied as tablets or oral elixirs to either supplement an intravenousadministration, or to ease home usage of the drug if the patient isself-administering the chemotherapeutic regimen.

Because some chemotherapeutic agents can induce emesis over extendedperiods of several days even when they are administered only once, itwould be desirable to administer an emesis-inhibiting drug such as a5-HT₃ antagonist every day until the risk of emesis has substantiallysubsided. The present class of 5-HT₃ antagonists has not provenespecially helpful meeting this need, however, because the 5-HT₃receptor antagonists currently marketed have proven to be less effectivein controlling delayed nausea and vomiting than they are at controllingacute emesis. Sabra, K, Choice of a 5HT ₃ Receptor Antagonist for theHospital Formulary. EHP, October 1996; 2 (suppl 1):S19-24.

Recently, clinical investigations have been made concerningpalonosetron, a new 5-HT₃ receptor antagonist reported in U.S. Pat. No.5,202,333. These investigations have shown that the drug is an order ofmagnitude more potent than most existing 5-HT₃ receptor antagonists, hasa surprising half-life of about 40 hours, and is effective to reducedelayed-onset nausea induced by chemotherapeutic agents. However,formulating palonosetron in liquid formulations has not proven an easytask, typically due to shelf-stability issues. U.S. Pat. No. 5,202,333discloses an intravenous formulation of palonosetron in example 13 thatcontains the following ingredients:

Ingredient Mg Palonosetron HCI 10-100 mg. Dextrose Monohydrate q.s. tomake Isotonic Citric Acid Monohydrate 1.05 mg. Sodium Hydroxide 0.18 mg.WFJ To 1.0 ml.

The formulation has a pH of 3.7 and a shelf stability of less than the1-2 year time period required by health authorities in variouscountries.

Ondansetron, its uses, and medicaments made with ondansetron aredisclosed in U.S. Pat. Nos. 4,695,578, 4,753,789, 4,929,632, 5,240,954,5,344,658, 5,578,628, 5,578,632, 5,922,749, 5,622,720, 5,955,488, and6,063,802. Commercially it is distributed by GlaxoSmithKline as Zofran®and is indicated for prevention of postoperative nausea and vomiting(PONV), cancer chemotherapy-induced nausea and vomiting (CINV), andradiotherapy-induced nausea and vomiting (RINV) and it is available asan injection, tablets and solution, and as Zofran ODT® (ondansetron)Orally Disintegrating Tablets.

Granisetron, its uses, and medicaments made with granisetron aredisclosed in U.S. Pat. Nos. 4,886,808, 4,937,247, 5,034,398 and6,294,548. Commercially it is distributed by Roche Laboratories Inc. asKytril®, indicated for the prevention of nausea and vomiting associatedwith chemotherapy or radiation therapy, and is offered in tablet form,oral solution, and as an injection.

Alosetron, its uses, and medicaments made with alosetron are disclosedin U.S. Pat. Nos. 5,360,800 and 6,284,770. Commercially it isdistributed by GlaxoSmithKline as Lotronex®.

Tropisetron is commercially available as Navoban® (Novartis)CAS-89565-68-4 (tropisetron); CAS-105826-92-4 (tropisetronhydrochloride) and it is indicated for treatment of PONV and CINV.

Dolasetron, its uses, and medicaments made with ondansetron aredisclosed in U.S. Pat. Nos. 5,011,846, and 4,906,755. Commercially it isdistributed by Aventis Pharmaceuticals Inc. as Anzemet®, indicated forprevention of both PONV and CINV, and it is offered in the form of atablet or an intravenous solution.

Therefore, there exists a need for a palonosetron formulation withincreased stability and thereby increased shelf life. There also existsa need for an appropriate range of concentrations for both the 5-HT₃receptor antagonist and its pharmaceutically acceptable carriers thatwould facilitate making a formulation with this increased stability.

It is an object of the present invention to provide a formulation ofPalonosetron hydrochloride with increased pharmaceutical stability forpreventing and/or reducing emesis.

It is another object of the invention to provide an acceptable range ofconcentrations which will stabilize a formulation containingPalonosetron hydrochloride.

It is a further object of the invention to provide a formulation ofPalonosetron which would allow for prolonged storage.

It is also an object of the invention to provide a formulation ofPalonosetron which would allow terminal sterilization.

SUMMARY OF THE INVENTION

The inventors have made a series of discoveries that support asurprisingly effective and versatile formulation for the treatment andprevention of emesis using palonosetron. These formulations are shelfstable for periods greater than 24 months at room temperature, and thuscan be stored without refrigeration, and manufactured using non-aseptic,terminal sterilization processes.

In one aspect, the inventors have discovered that formulations whichinclude the active ingredient palonosetron require in some instancesonly 1/10^(th) the amount of other previously known compounds fortreating emesis, which surprisingly allows the use of concentrations ofpalonosetron far below those that would ordinarily be expected. Thus, inone embodiment the invention provides a pharmaceutically stable solutionfor preventing or reducing emesis comprising a) from about 0.01 mg/mL toabout 5 mg/mL palonosetron or a pharmaceutically acceptable saltthereof; and b) a pharmaceutically acceptable carrier.

The inventors have further discovered that by adjusting theformulation's pH and/or excipient concentrations it is possible toincrease the stability of palonosetron formulations. Therefore, inanother embodiment, the invention provides a pharmaceutically stablesolution for preventing or reducing emesis comprising a) palonosetron ora pharmaceutically acceptable salt thereof; and b) a pharmaceuticallyacceptable carrier, at a pH from about 4.0 to about 6.0. In anotherembodiment the invention provides a pharmaceutically stable solution forpreventing or reducing emesis comprising from about 0.01 to about 5.0mg/ml palonosetron or a pharmaceutically acceptable salt thereof; fromabout 10 to about 100 millimoles citrate buffer; and from about 0.005 toabout 1.0 mg/ml EDTA.

The inventors have further discovered that the addition of mannitol anda chelating agent can increase the stability of palonosetronformulations. Therefore, in still another embodiment the inventionprovides a pharmaceutically stable solution for preventing or reducingemesis comprising a) palonosetron or a pharmaceutically acceptable saltthereof and b) a pharmaceutically acceptable carrier, wherein thepharmaceutically acceptable carrier comprises a chelating agent andmannitol.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Vial” means a small glass container sealed with the most suitablestopper and seal, other suitable primary containers may be used, forinstance, but not limited to, pre-filled syringes. Vial also means asealed container of medication that is used one time only, and includesbreakable and non-breakable glass vials, breakable plastic vials,miniature screw-top jars, and any other type of container of a sizecapable of holding only one unit dose of palonosetron (typically about 5mls.).

Throughout this specification the word “comprise,” or variations such as“comprises” or “comprising,” will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps

“Palonosetron” means(3aS)-2,3,3a,4,5,6-Hexahydro-2-[(S)-1-Azabicyclo[2.2.2]oct-3-yl]2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline,and is preferably present as the monohydrochloride. Palonosetronmonohydrochloride can be represented by the following chemicalstructure:

Concentrations—When concentrations of palonosetron are given herein, theconcentration is measured in terms of the weight of the free base.Concentrations of all other ingredients are given based on the weight ofingredient added to the solution.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts which arepharmaceutically acceptable, as defined above, and which possess thedesired pharmacological activity. Such salts include acid addition saltsformed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or withorganic acids such as acetic acid, propionic acid, hexanoic acid,heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2,-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acidp-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonicacid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like.

In addition, pharmaceutically acceptable salts may be formed when anacidic proton present is capable of reacting with inorganic or organicbases. Acceptable inorganic bases include sodium hydroxide, sodiumcarbonate, potassium hydroxide, aluminum hydroxide and calciumhydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

Discussion

The fact that palonosetron can be formulated in some instances atconcentrations of only about 1/10^(th) the amount of other previouslyknown compounds for treating emesis, surprisingly allows the use ofconcentrations of palonosetron far below those that would ordinarily beexpected. Thus, in one embodiment the invention provides apharmaceutically stable solution for preventing or reducing emesiscomprising a) from about 0.01 mg/mL to about 5 mg/mL palonosetron or apharmaceutically acceptable salt thereof; and b) a pharmaceuticallyacceptable carrier. Similarly, in another embodiment the inventionprovides a method of formulating a pharmaceutically stable solution ofpalonosetron comprising admixing from about 0.01 mg/mL to about 5 mg/mLpalonosetron or a pharmaceutically acceptable salt thereof; with apharmaceutically acceptable carrier. In alternative embodiments, theformulation includes palonosetron or a pharmaceutically acceptable saltthereof in a concentration from about 0.02 mg/mL to about 1.0 mg/mL,from about 0.03 mg/mL to about 0.2 mg/mL, and most optimally about 0.05mg/ml.

A particular advantage associated with the lower dosages of intravenouspalonosetron is the ability to administer the drug in a singleintravenous bolus over a short, discrete time period. This time periodgenerally extends from about 10 to about 60 seconds, or about 10 toabout 40 seconds, and most preferably is about 10 to 30 seconds. In oneparticular embodiment the palonosetron is supplied in vials thatcomprise 5 ml. of solution, which equates to about 0.25 mg ofpalonosetron at a concentration of about 0.05 mg/ml.

The inventors have further discovered that by adjusting theformulation's pH and/or excipient concentrations it is possible toincrease the stability of palonosetron formulations. Therefore, inanother embodiment, the invention provides a pharmaceutically stablesolution for preventing or reducing emesis comprising a) palonosetron ora pharmaceutically acceptable salt thereof; and b) a pharmaceuticallyacceptable carrier, at a pH from about 4.0 to about 6.0. Similarly, inanother embodiment the invention provides a method of formulating apharmaceutically stable solution of palonosetron comprising admixing a)palonosetron or a pharmaceutically acceptable salt thereof; and b) apharmaceutically acceptable carrier, at a pH from about 4.0 to about6.0. In alternative embodiments, the pH is from about 4.5 to about 5.5,and most optimally about 5.0. There are many examples to those of skillin the art of suitable solutions to adjust the pH of a formulation. Twoexemplary solutions are sodium hydroxide and hydrochloric acid solution,either of which could be used to adjust the pH of the formulation.

In another embodiment the invention provides a pharmaceutically stablesolution for preventing or reducing emesis comprising from about 0.01 toabout 5.0 mg/ml palonosetron or a pharmaceutically acceptable saltthereof and (i) from about 10 to about 100 millimoles citrate buffer,and/or (ii) from about 0.005 to about 1.0 mg/ml EDTA. Similarly, inanother embodiment the invention provides a method of formulating apharmaceutically stable solution of palonosetron comprising admixingfrom about 0.01 to about 5.0 mg/ml palonosetron or a pharmaceuticallyacceptable salt thereof and (i) from about 10 to about 100 millimolescitrate buffer, and/or (ii) from about 0.005 to about 1.0 mg/ml EDTA.The citrate buffer can be in the form of citric acid and/or a salt ofcitric acid such as trisodium citrate. In various embodiments, theranges of one or more of the foregoing ingredients can be modified asfollows:

-   -   The formulation may comprise palonosetron or a pharmaceutically        acceptable salt thereof in a concentration from about 0.02 mg/mL        to about 1.0 mg/mL, from about 0.03 mg/mL to about 0.2 mg/mL        palonosetron hydrochloride, and most optimally about 0.05 mg/ml.    -   The formulation may comprise citrate buffer in a concentration        of from about 10 to about 40 millimoles, or 15-30 millimoles.    -   The formulation may comprise EDTA in a concentration of from        about 0.005 mg/ml to about 1.0 mg/ml, or about 0.3 to about 0.7        mg/ml, and most optimally about 0.5 mg/ml.

The inventors have further discovered that the addition of mannitol anda chelating agent can increase the stability of palonosetronformulations. Therefore, in still another embodiment the inventionprovides a pharmaceutically stable solution for preventing or reducingemesis comprising a) palonosetron or a pharmaceutically acceptable saltthereof and b) a pharmaceutically acceptable carrier, wherein thepharmaceutically acceptable carrier comprises a chelating agent andmannitol. Similarly, in another embodiment the invention provides amethod of formulating a pharmaceutically stable solution of palonosetroncomprising admixing a) palonosetron or a pharmaceutically acceptablesalt thereof and b) a pharmaceutically acceptable carrier, wherein thepharmaceutically acceptable carrier comprises a chelating agent andmannitol. The chelating agent is preferably EDTA, and, in variousembodiments the chelating agent is present in a concentration of fromabout 0.005 to about 1.0 mg/mL or from about 0.05 mg/mL to about 1.0mg/mL or from about 0.3 to about 0.7 mg/ml, or most optimally about 0.5mg/mL. In various embodiments the mannitol is present in a concentrationof from about 10.0 mg/ml to about 80.0 mg/ml, from about 20.0 mg/mL toabout 60.0 mg/ml, or from about 40.0 to about 45.0 mg/ml.

Injectable formulations are typically formulated as aqueous solutions inwhich water is the primary excipient. Oral formulations will differ frominjectable formulations generally by the additional presence offlavoring agents, coloring agents, or viscosity agents. Natural orsynthetic sweeteners include, among others, mannitol, sorbitol,saccharose, saccharine, aspartame, acelsulphame K, or cyclamate. Theseagents are generally present in concentrations in excess of 100 mg/ml or250 mg/ml when used as sweetening agents, in contrast to the 41.5 mg/mlconcentration of mannitol described in some of the embodiments of theinvention, in which mannitol is acting simply as a tonicifying agent.

The formulations of the present invention are particularly suited foruse in injectable and oral liquid formulations, but it will beunderstood that the solutions may have alternative uses. For example,they may be used as intermediates in the preparation of otherpharmaceutical dosage forms. Similarly, they may have other routes ofadministration including intranasal or inhalation. Injectableformulations may take any route including intramuscular, intravenous orsubcutaneous.

Still further embodiments relate to improvements in the ease with whichthe palonosetron formulation can be stored or manufactured. Inparticular, the inventors have discovered that the formulations of thepresent invention allow storage of the product for extended periods atroom temperature. Thus, in yet another embodiment the invention providesa method of storing one or more containers in which are contained asolution of palonosetron or a pharmaceutically acceptable salt thereofcomprising: a) providing a room comprising said one or more containers;b) adjusting or maintaining the temperature of the room at greater thanabout ten, 15, or 20 degrees celcius; and c) storing said containers insaid room for one month, 3 months, 6 months, one year, 18 months, 24months or more (but preferably not exceeding 36 months), wherein (i) thepalonosetron or pharmaceutical salt thereof is present in aconcentration of from about 0.01 mg/mL to about 5.0 mg/mL, (ii) the pHof the solution is from about 4.0 to about 6.0, (iii) the solutioncomprises from about 0.01 to about 5.0 mg/ml palonosetron or apharmaceutically acceptable salt thereof, from about 10 to about 100millimoles citrate buffer and from about 0.005 to about 1.0 mg/ml EDTA,(iv) the solution comprises a chelating agent, or (v) the solutioncomprises from about 10 to about 100 milliMoles of a citrate buffer.

The stability of the foregoing formulations also lends itself well toterminal sterilization processes in the manufacturing process.Therefore, in still another embodiment the invention provides a methodof filling a container in which is contained a solution of palonosetronor a pharmaceutically acceptable salt thereof comprising: a) providingone or more sterile open containers (preferably 5 ml. vials); b) fillingsaid containers with a solution of palonosetron in a non-asepticenvironment; c) sealing said filled containers; and d) sterilizing saidsealed, filled containers, wherein (i) the palonosetron orpharmaceutical salt thereof is present in a concentration of from about0.01 mg/mL to about 5 mg/mL, (ii) the pH of the solution is from about4.0 to about 6.0, (iii) the solution comprises from about 0.01 to about5.0 mg/ml palonosetron or a pharmaceutically acceptable salt thereof,from about 10 to about 100 millimoles citrate buffer and from about0.005 to about 1.0 mg/ml EDTA, (iv) the solution comprises a chelatingagent, or (v) the solution comprises from about 10 to about 100milliMoles of a citrate buffer.

EXAMPLES Example 1 Stabilizing pH

A study was conducted to determine the effect of pH on formulationscontaining palonosetron hydrochloride, measuring the stability at 80° C.at pH 2.0, 5.0, 7.4, and 10.0. The results indicated that palonosetronhydrochloride is most stable at pH 5.0.

Example 2 Stabilizing Concentration Ranges

A formulation optimization study was performed using an experimentaldesign software. Twenty-four lots of drug product were analyzed toinvestigate the appropriate concentration ranges for palonosetronhydrochloride (0.05 mg/mL to 5.0 mg/mL), citrate buffer (0 to 80 mM) andEDTA (0 to 0.10%). The level of EDTA and citrate buffer were selectedbased on the optimal formulation, which was shown to be formulated withEDTA 0.05% and 20 mM citrate buffer at pH 5.0. The results of this studyindicated that palonosetron concentration was also a critical factor inchemical stability, with greatest stability seen at the lowestpalonosetron concentrations.

Example 3 Tonicifying Agent

Formulations of palonosetron hydrochloride in citrate buffer wereprepared including either a) sodium chloride or b) mannitol. Thepalonosetron hydrochloride formulation including mannitol showedsuperior stability. The optimum level of mannitol required for anisotonic solution was found to be 4.15%.

Example 4 Formulation I

The following is a representative pharmaceutical formulation containingpalonosetron that is useful for intravenous formulations, or otherliquid formulations of the drug.

Ingredient mg/mL Palonosetron Hydrochloride 0.05* Mannitol 41.5 EDTA 0.5Trisodium citrate 3.7 Citric acid 1.56 WFJ q.s. to 1 ml Sodium hydroxidesolution and/or pH 5.0 ± 0.5 hydrochloric acid solution *calculated as afree base

Example 5 Formulation II

The following is a representative pharmaceutical formulation containingpalonosetron that is useful for oral formulations, or other liquidformulations of the drug.

Ingredient mg/mL Palonosetron Hydrochloride 0.05* Mannitol 150 EDTA 0.5Trisodium citrate 3.7 Citric acid 1.56 WFJ q.s. to 1 ml Sodium hydroxidesolution and/or pH 5.0 ± 0.5 hydrochloric acid solution Flavoring q.s.*calculated as a free base

Example 6 Stability of Palonosetron without Dexamethasone

The physical and chemical stability of palonosetron HCl was studies inconcentrations of 5 μg/mL and 30 μg/mL in 5% dextrose injection, 0.9%sodium chloride injection, 5% dextrose in 0.45% sodium chlorideinjection, and dextrose 5% in lactated Ringer's injection. Theadmixtures were evaluated over 14 days at 4° C. in the dark and for 48hours at 23° C. under fluorescent light.

Test samples of palonosetron HCl were prepared in polyvinyl chloride(PVC) bags of the infusion solutions at concentrations of 5 and 30μg/mL. Evaluations for physical and chemical stability were performed onsamples taken initially and after 1, 3, 5, 7, and 14 days of storage at4° C. and after 1, 4, 24, and 48 hours at 23° C. Physical stability wasassessed using visual observation in normal room light and using ahigh-intensity monodirectional light beam. In addition, turbidity andparticle content were measured electronically. Chemical stability of thedrug was evaluated by using a stability-indicating high performanceliquid chromatographic (HPLC) analytical technique.

All samples were physically stable throughout the study. The solutionremained clear, and little or no change in particulate burden and hazelevel were found. Additionally, little or no loss of palonosetron HCloccurred in any of the samples at either temperature throughout theentire study period.

Example 7 Stability of Palonosetron with Dexamethasone

The physical and chemical stability of palonosetron HCl 0.25 mg admixedwith dexamethasone (as sodium phosphate) 10 mg or 20 mg in 5% dextroseinjection or 0.9% sodium chloride injection in polyvinyl chloride (PVC)minibags, and also admixed with dexamethasone (as sodium phosphate) 3.3mg in 5% dextrose injection or 0.9% sodium chloride injection inpolypropylene syringes at 4° C. in the dark for 14 days and at 23° C.exposed to normal laboratory fluorescent light over 48 hours, wasstudied.

Test samples of palonosetron HCl 5 μg/mL with dexamethasone (as sodiumphosphate) 0.2 mg/mL and also 0.4 mg/mL were prepared in polyvinylchloride (PVC) minibags of each infusion solution. Additionally,palonosetron HCl 25 μg/mL with dexamethasone (as sodium phosphate) 0.33mg/mL in each infusion solution were prepared as 10 mL of test solutionin 20-mL polypropylene syringes. Evaluations for physical and chemicalstability were performed on samples taken initially and after 1, 3, 7,and 14 days of storage at 4° C. and after 1, 4, 24, and 48 hours at 23°C. Physical stability was assessed using visual observation in normalroom light and using a high-intensity monodirectional light beam. Inaddition, turbidity and particle content were measured electronically.Chemical stability of the drug was evaluated by using astability-indicating high performance liquid chromatographic (HPLC)analytical technique.

All samples were physically compatible throughout the study. Thesolutions remained clear, and little or no change in particulate burdenand haze level were found. Additionally, little or no loss ofpalonosetron HCl and dexamethasone occurred in any of the samples ateither temperature throughout the entire study period.

Example 8 Formulation III

The following is a representative pharmaceutical formulation andcontainer closure for palonosetron that is useful for intravenousinfusion formulations.

Ingredient Amount (mg) Palonosetron Hydrochloride  0.75^(a)) SodiumChloride 450.0 EDTA  2.5 Sodium citrate  18.5 Citric acid monohydrate 7.8 WFJ q.s. to 50 mL Sodium hydroxide solution and/or pH 4.8 ± 0.5hydrochloric acid solution Container closure system plasticcontainer^(b)) plus rubber stopper^(c)) ^(a))Calculated based on theweight of free base ^(b))Polyethylene multilayer film infusion bag.^(c))Isoprene rubber stopper.

This invention has been described with reference to its preferredembodiments. Variations and modifications of the invention will beobvious to those skilled in the art from the foregoing detaileddescription of the invention.

What is claimed is:
 1. A formulation comprising a pharmaceutical sterileaqueous intravenous solution, wherein said pharmaceutical sterileaqueous intravenous solution comprises palonosetron or apharmaceutically acceptable salt thereof in an amount of 0.25 mg and aconcentration of from 0.03 mg/mL to 0.2 mg/mL based on the weight of thepalonosetron free base.
 2. The formulation of claim 1, wherein saidpharmaceutical sterile aqueous intravenous solution has a pH of from 4to
 6. 3. The formulation of claim 1, wherein said pharmaceutical sterileaqueous intravenous solution has a pH of 5.0±0.5.
 4. A method ofmanufacturing a finished container of a pharmaceutical formulationcomprising palonosetron or a pharmaceutically acceptable salt thereof,said method comprising: a) providing an open container; b) filling saidcontainer with an aqueous intravenous solution comprising saidpalonosetron or pharmaceutically acceptable salt thereof in an amount of0.25 mg and a concentration of from 0.03 mg/mL to 0.2 mg/mL based on theweight of the palonosetron free base; c) sealing said filled container;and d) terminally sterilizing said sealed, filled container to obtainsaid finished container.
 5. The method of claim 4, wherein said aqueousintravenous solution has a pH of from 4 to
 6. 6. The method of claim 4,wherein said aqueous intravenous solution has a pH of 5.0±0.5.
 7. Afinished container of palonosetron or a pharmaceutically acceptable saltthereof, manufactured and terminally sterilized by the process of claim4.
 8. The finished container of claim 7, wherein said aqueousintravenous solution has a pH of from 4 to
 6. 9. The finished containerof claim 7, wherein said aqueous intravenous solution has a pH of5.0±0.5.